Hematology Flashcards
Virchows triad for thrombosis?
blood
vessel wall - antithrombotic normally, secretes anticoagulants and antiplatelet factors. inflammation and injury makes it Prothrombotic
blood flow - stasis:
Immobility = Surgery, Paraparesis Travel
Compression = Tumour, pregnancy
Viscosity = Polycythaemia, Paraprotein
Congenital vascular abnormalities
state immediate anticoagulant therapies and their mechanisms
Eg heparin mechanism and how to reverse
heparin - potentiates antithrombin. reverse with protamine
direct Xa inhibitors and IIa inhibitors
acute leukemia features?
rapid onset
blast cells (immature cells) - high nucleus:cytoplasm ratio
bone marrow failure ->anemia, neutropenia (infections), thrombocytopenia (bleeding)
mutation in chronic myeloid leukemia occurs at which level?
pluripotent hematopoeitic stem cells
Acute myeloid leukemia AML
stats?
pathology?
increases with age
40% in adults
many have abberations in chromosome count or structure eg t(8,21) -> RUNX1/RUNX1T1 fusion
t(15,17) -> acute promyelocytic lueukemia!!
inv(16) -> may see eosinophilia
two hits
type 1 - promote proliferation and survival
type 2 - block differentiation
t(15,17) translocation occurs in?
Clinical effect?
most important diagnostic test?
acute promyelocytic leukemia - must be treated quickly.
can cause massive hemorrhage eg cerebral hemorrhage
accumulation of promyelocytes NOT blast cells
causes DIC!
hypergranular, multiple auer rods!!!
may habve bilobed nuclei (variant apl)
cytogenetic analysis/molecular/fish -> looking for translocation
what chromosomal duplications are common in AML?
+8
+21 (downs)
in a patient with AML with normal chromosomes, what molecular abnormality could have occured?
point mutation NPM1, CEBPA
partial duplication FLT3
loss of tumour suppressor genes
AML vs ALL?
Which is Mpo +ve?
What are the different cell markers expressed by these?
AML has fine granules in cytoplasm - you probably cant see them. has aueur rods (pathoneumonic of myeloid neoplasm)
cytochemical staining:
Myeloperoxidase -> stains for Myeloid cells (tell from name) -> brown stain
sudan black stain -> +ve myeloid cells
non-specific esterase -> +ve myeloid cells
Immunophenotyping -> identify cell type based surface or cytoplasmic antigen only expressed on lymphoid vs myeloid cells. xamples include
- immunocytochemistry/immunohistochemistry = using antibodies + florescent enzyme
- flow cytometry - will tell you markers eg CD13!! AND CD33!! expressed by myeloid cells -> AML
(ALL is Tdt +ve -> T cells express CD3!, B cells CD19!, CD10!)
AML features?
bone marrow failure ->anemia, neutropenia (infections - can be as serious as septic shock), thrombocytopenia (bleeding)
inflitration of tissues by leukemic cells -> spleenomegaly, hepatomegaly, gum infiltration if monocytic, lymphadenopathy occasionally
Skin/CNS disease eg cranial nerve palsy
DIC -> vascular obstruction, gangrene
hyper viscosity of wbc = retinal hemorrhage
AML diagnosis
blood film!
- blasts and auer rods
- if no auer rods, immunophotyping to distinguish AML from ALL
- if aleukemic lukemia suspected = bone marrow aspirate
once diagnosed, do cytogenetic studies to guide treatment
AML treatment
Red cells, platelets, FFP/Cryoprecipitate if DIC, antibiotics if infection, allopurinol if uric acid release from chemo
combination chemo
all trans retinoic acid for acute promyelocytic leukemia
ALL stats?
features?
diagnosis?
occurs in children
most common childhood malignancy!. AML rare in child
bone marrow failure: anemia (pallor), neutropenia, thrombocytopenia (bruising)
local infiltration: lymphadenopathy (more prominent than AML), thymic inflitration (mediastinal mass!! - this does not occur in AML) if T lineage may occur, spleenomegaly, hepatomegaly
bone pain!
CNS, testes, kidneys
blood film
immunophenotype - important as T-ALL and B-ALL are treated differently. best technique to diagnose
where does ALL start?
which patients have better prognosis?
treatment
B-ALL in bone marrow
T-ALL can start in thymus -> thymic enlargement -> mediastinal mass
patients with hyperdiploidy eg t(12,21) t(1,19)
patients with t(9,22) due to tyrosine kinase inhibitors/ imatinib that inhibit BCR-ABL-> which is philadelphia cchromosome also seen in CML
chemo
CNS directed therapy as lymphoblasts can enter CSF
supportive care: blood products, antibiotics
how are childrens FBCs different from adults?
how are newborn babies different from adults?
how is sthe experience of illness different for kids?
children have higher lymphocyte counts and MCVs
have LOWER hemoglobin concs
newborns have higher lymphoctytes and MCVs
HIGHER hemoglobin conc
kids more likely to respond with lymphocytosis
disease or treatment can cause delayed puberty and growth retardation may happen in kids
neonate reference range for FBC different from a child and adult
causes of anemia in fetus
parvovirus infection in mother
shared twin placenta
fetal to maternal transmission
causes of polycythemia in fetus or neonate
placental insufficiency
itrauterine hypoxia
twin to twin transfusion
Why does sickle cell anemia not manifest at birth?
it is a Beta chain defect not alpha chain
clinical features manifest as hemoglobin F synthesis decreases and BetaS and hemoglobin S production increase
why is sickle cell anemia different in child vs adult?
What conditions occur only in child?
in child, red marrow extends throughout skeleton and is susceptible to infarction
in adult, it is confined to axial skeleton
thus hand-foot syndrome only seen in children, typically in fist 2 years
infant still has a functioning spleen so splenic sequestration can occur -> severe anemia, shock
in adults, spleen undergoes multiple infarctions and thus no longer succeptible to splenic sequestration but hypospleenism can occur
red cell aplasia more common in children due to highr liklihood of coming across parvovirus as a child
stroke more common in children - smaller cerebral arteries
seen in children:
- hand foot syndrome
- splenic sequestration
-
sickle cell anemia management in child?
vaccinate
educate important to give penicillin and folic acid to children
if siblings with sickle cell anemia present simultaneously with severe anaemia and low reticulocyte count, what is the likely diagnosis?
Parvovirus B19
how does blood film in sickle cell anemia and sickle cell trait differ?
sickle cells wont be seen in blood film for sickle cell trait
what is beta thalasemia?
how does heterozygous and homozygous present?
reduced synthesis of Beta globin chain and therefore hemoglobin A
heterozygous = harmless
homozygous = severe anemia, fatal without blood transfusion in first few years
homozygous
anemia -> heart failure, growth retardation
erothropoeitic drive -> bone expansion, hepatomegaly, spleenomegaly (extramedullary hematopoeisis)
iron overload -> heart failure, gonadal failure
beta thalesemmia major treatment?
blood transfusion to maintain Hb
Will cause iron overload -> desfeiroxamine for chelation
causes of hemolytic anemia in child?
inherited
acquired
- hemolytic disease of newborn (ABO or Rh antibodies)
- defects in red cell membrane (hereditary spherocytosis and elliptocytosis), red cell enzymes (glycolytic pathway, pentose shunt/G6PD which mainly affects males), hemoglobin molecule
how to diagnose hemolytic anemia?
anemia
signs of red blood cell breakdown - jaundice, spleenomegaly, increased unconjugated bilirubin
increased reticulocyte count? bone expansion?
abnormal red cells in blood film?
how can hemophila A and B present
differential diagnoses?
investigations?
bleeding following circumcision
hemarthroses when starting to walk
bruises
post traumatic bleeding
differentials: inherited thrombocytopenia or platelet function defect, acquired defects eg acute leukemia, itp, non accidental injury, henoch schonlein purpura
blood film
platelet count
coagulation screen
assay of relevant factors
questions to ask to rule out inherited defects of coagulation
managment?
umbilical cord bleeding after cut?
bleeding with heel prick test?
hematomas after vitamin k injection or vaccinations?
bleeding after circumcision?
family history
treating of bleeding
prophylactic anticoagulants
VWD presentation?
investigation?
differential diagnosis?
treatment?
mucosal bleeding - affects platelet FUNCTION, not count
bruises
post trauma bleeding
coagulation screen - elongated aPTT
factor 8 assay
FH history
bleeding time
differential diagnosis is hemophila A as factor 8 level is reduced in both diseases
lower purity factor 8 concentrate
1 year old with joint bleeding, HB WBC and platelet count normal. aPTT prolonged, normal PT, bleeding time normal.
what is the diagnosis?
hemophilia A most likely
(because 5x more common than hemophila B_
ITP presentation?
diagnosis?
petechiae
bruises
blood blisters in mouth
history - febrile illness
drugs
blood count film - confirm thrombocytopenia
bone marrow aspirate - not usually needed
treatment is observation
corticosteroids if serious hemorrhage or blisters in mouth
high dose intravenous immunoglobulin
intravenous anti Rh D if RH positive
what factor is involved in formation of stable platelet plug?
VWF
describe 2 ways in which platelet adhesion to endothelium occurs
directly through glycoprotein 1A
through glycoprotein 1B with assistance of VWF
describe how platelet aggregation occurs
after adhesion, release of ADP and thromboxane
which promote aggregation via glycoprotein 2B 3A (which allows fibrinogen to bind/fibrinogen receptor)
thromboxane A2 role?
prostacyclin PGI2 role?
- induces platelet aggregation
- inhibits platelet aggregation
thrombin function?
cleaves fibrinogen to fibrin!! (stable clot)
activates platelets
activates clotting factors
mechanism of blood clot removal? Describe natural body process
plasminogen is converted to plasmin by tpa
plasmin cleaves fibrin
how is thrombin inhibited?
effect of heparin?
antithrombin 3 binds it
auguments effect of antithrombin
protein C and protein S function?
How does Factor V leiden present?
when activated, they are antithrombotic as they degrade factor V and Factor 8
thrombomodulin binds protein C activates it, APC binds protein S to cleave factor V and 8
mutation in factor 5 making it resistant to breakdown by APC -> thrombosis
causes of APC resistance?
factor 5 leiden
high levels of factor 8
state 2 genetic causes of bleeding disorders
state 2 acquired causes
1. platelet abnormalities
2. clotting factor deficiencies eg hemophilia
3. vascular/endothelium - scurvy
1. liver disease (site of clotting factor synthesis)
2. vitamin K deficiency
3. autoimmune destruction of platelets
most common cause of thrombocytopenia?
immune mediated is most common cause
- idiopathic most common
- drugs
- connective tissue disease
- lymphoproliferative disease eg leukemia
- sarcoidosis
non immune:
- DIC
- Microangiopathic hemolytic anemia
ITP managment?
platelet count between 20 -50,000 - you only treat if bleeding -> steroids, IVIG
count less than 20,000 -> whether bleeding or not -> you treat as above and hospitalise
describe two causes of thrombocytopenia recognized through blood film
B12 deficiency - Large rbc/macrocytosis
AML - myeolid blasts
hemophilia symptoms
hemarthrosis - fixed joints
soft tissue hematomas: muscle atrophy, shortened tendons
bleeding in urinary tracts, CNS, neck
causes of Vitamin K deficiency?
malabsorption
malnutrition
biliary obstruction
antibiotics
common causes of DIC
sepsis - eg meningitis
trauma
malignancy
toxins - eg snake venom
blood film - spliced rbcs
most common cause of intravascular hemolytic anemia?
malaria
signs of hemolytic anemia?
anemia
increased reticulocyte
increased folate requirement
susceptibility to parvovirus B19 - aplastic crisis, low or absent reticulocyte count - only early forms of RBC seen in marrow as differentiation arrested
gallstones -> risk increases with co existence of Gilberts Syndrome
iron overload -> seen on liver biopsy
clinical
- pallor
- jaundice
- spleenomegaly
- pigmenturia eg in hemoglobinuria
- Family history
biochemical findings in intravascular hemolysis?
increased LDH
decreased haptoglobins
hereditary spherocytosis
blood film findings?
test?
ankyrin
Beta spectrin
smaller cells, lack central pallor, MCHC increased
osmotic fragility
dye binding test
hereditary elliptocytosis
blood film findings?
alpha spectrin
beta spectrin
elliptical cells
hereditary pyropoikilocytosis = homozygous form = severe anemia
G6PD deficiency manifestations?
triggers?
neonatal jaundice -> kernicterus
acute hemolytic anemia
bite cells, hemighost cells, heinz bodies
when patient is well, blood film typically unremarkable
antimalarias - primaquine, dapsone
sulphonamides, ciprafloxacin, nitrofurantoin
vitamin K
pyruvate kinase deficiency blood film finding?
short projections on red blood cells (speculated red blood cells/echinocytes) -> increase after spleenectomy
pyrimidine 5 nucleotidase deficiency findings on blood film?
basophilic stippling
first line investigations for patient with unexplained hemolytic anemia?
dat test - detect immunoglobulins on rbcs/ exclude autoimmune hemolysis
urinary hemosiderin/hemoglobin - looking for evidence of intravascular hemolysis
osmotic fragility
G6PD +/- PK activity
electrophoresis -> hemoglobin causes
heinz body stain -> oxidative hemolysis eg G6PD, hemoglobin hammersmith
Hams test/flow cytometry -> paroxysmal nocturnal hemoglobinuria
thick and thin blood film - malaria
hemolytic anaemia management?
folic acid supplementation
avoid precipitants
red cell transfusion
immunisations against blood borne viruses -> hep A and hep B
cholecystectomy or spleenectomy if indicated
indications for spleenectomy?
transfusion dependence
growth delay
physical limitation hb < or equal to
hypersplenism which is symptomatic
not before 3 and aim to do before age 10 to not delay growth
give examples of situations in which you MUST order a blood film (allows for evaluation of rbcs, wbcs and platelets)
1. An unexpected life-threatening condition - malaria (parasites seen - also presents w thrombocytopenia, fever), babesiosis (intra and extracellular parasites seen, maltese cross shape seen, endemic to US, immunosuppressed RF), HIV positive and unwell - could be disseminated histoplasmosis.
2. ACUTE ANEAMIA- megaloblastic, paroxysmal cold hemoglobinuria(agglutination, spherocytes, erythrophagocytosis,), Hereditary spherocytosis (if reticulocyte is low, suggests parvovirus B19 infection). G6PD and hemaglobinuria
3. ITP and TTP (thrombotic thrombocytopenic purpura)
4. ACUTE LEUKEMIA
5. BURKITT LYMPHOMA (associated with AIDS)
6. ACUTE KIDNEY INJURY. could be due to:
- Multiple myeloma
- Haemolytic uraemic syndrome
- Thrombotic thrombocytopenic purpura
- Tumour lysis syndrome in high grade haematological neoplasms
- AML or lymphoma with hyperuricaemia
7. INFECTION-
malaria
dog bite (capnocytophaga canimorsis)
babesia
borrelia infection in north african child
(learn how these infections look on blood film)
if a patient with ITP and low platelets is given IVIG and later notes red urine, what is the likely cause?
hemoglobinuria - blood film may show spherocytes and polychromatic macrocytes suggesting hemolysis.
pathology = acute intravascular hemolysis resulting from antiA in IVIG, causing hemaglobinuria
rule out hematuria by centrifuging urine sample - if layers are formed/ separate to give a
always do a blood count and blood film with patient with new petechia or bruising.
what are some blood film explanations for thrombocytopenia?
Meningococcal sepsis - neutrophils will show basophilic inclusions of bacteria - MEDICAL EMERGENCY
thrombotic thrombocytopenic purpura - platelets not seen, fragmented rbcs!!!!!/shistyocytes - MEDICAL EMERGENCY - MAHA, thrombocytopenia, acute kidney injury, low ADAMTS13, headache abdominal pain due to thrombi.
HELLP Syndrome - MEDICAL EMERGENCY, deliver baby - blood film shows no platelets - MUST DO blood film as could be Malaria!
TTP management?
plasma exchange and corticosteroids
do not transfuse platelets - worsen condition
acute promyelocytic anemia
management
platelets and correction of hypofibrinogenaemia
immediate treatment with alltransretinoic even if diagnosis not confirmed
emergency
other causes of AML are less urgent unless there is leucostasis or SVC obstruction
when is acute lymphoblastic leukemia urgent?
when there is hyperleukocytosis
or SVC obstruction in T-ALL
macrocytic aneamia/folate deficiency + howell jolly bodies makes you think?
coeliac disease
spleenomegaly and damage -> howell jolly bodies
iron deficiency is what until proven otherwise?
bleeding (possibly cancer)
leucoerythroblastic anemia features?
causes?
anemia with these on blood film:
- teardrop rbcs
- nucleated rbcs -should only be in bone marrow
- immature myeloid cells - should only be in bone marrow
caused by bone marrow infiltration:
1. malignancy - hematopoietic (eg leukemia) or non hematopoietic eg metastatic breast cancer
2. Myelofibrosis - Massive spleen!!!!(differentiates from other causes), dry tap on BM aspirate
3. severe infection - miliary tb, severe fungal infection
immune hemolytic anemia features?
risk factors/causes?
spherocytes
+ve DAT test
cancer of immune system eg lymphoma, CLL
autoimmune - SLE
infection - mycoplasma
idiopathic
acquired non immune hemolytic anemia causes
malaria
MAHA
MAHA causes ?
blood film findings?
underlying adenocarcinoma
HUS
RBC fragments
thrombocytopenia
what to ask when you see an abnormal wbc count?
state some causes of elevated wbc
is it all lineages or a particular one eg eosinophils?
are there cells in peripheral blood that shouldnt be found there? - eg myeloblast, myelocytes
- acute leukemia
- chronic myeloid leukemia
- Infectious mono - EBV, CMV, toxoplasma
- oesinophilia
- reactive neutrophilia - infection(toxic granules/vacuoles but no immature cells seen if infection vs CML which has neutophila +myelocytes and basophils), steroids, inflammation eg pancreatitis/myocarditis, underlying neoplasia
causes of elevated LYMPHOCYTE count?
causes of reduced?
- Infectious mono - EBV, CMV, toxoplasma = atypical mature lymphocytes
- infectious hepatitis, rubella, herpes
- autoimmune disorders
- sarcoidosis
- CLL - small mature lymphocytes, smear cells
- ALL - immature/lymphoblasts
reduced:
- infection - HIV
- autoimmune
- inherited immune deficiency syndromes
- drugs - chemo
how to distinguish monoclonal lymphocytosis (blood cancer) vs reactive lymphocytosis (infection) through immunophenotyping of B cells
Kappa and Lambda 60:40 = healthy bone marrow, reactive lymphocytosis
Kappa only or Lambda only 99:1 = leukemia or lymphoma
female 39 with lymphoma stage 4 involving bone marrow, lymph nodes, liver
develops anemia, retciulocytosis, spherocyts
what could be the cause
could be anemia due to bone marrow inflitration - in this case would have low reticulocytes, DAT negative, if elevated biliuribin was conjugated will point away from hemolysis and towards liver mets. Leukoerythroblastic film will be seen
the answer is immune hemolytic anemia (cancer of immune system) - due to reticulocytosis and spherocytes not seen in bone marrow infiltration/leukoerythroblastic picture
Diagnosis of hematological cancers method
morphology
immunophenotype - flow cytometry or immunohistochemistry
cytogenetics - chromosomal abnormalities
molecular genetics - DNA mutations
what is lymphoma?
clinical presentation?
HL staging+values?
HL treatment?
cancer of lymphoid system/cells, typically of lymphatic system
bone marrow, thymus,(generative tissue) lymph nodes, spleen,(reactive tissue) blood
lymphadenopathy - cervical, axillary, mesenteric etc
spleenomegaly
compression of tubes-> ureter, bile duct, ivc etc
infiltration of organ-> eye, cns, liver failure
recurrent infection
constitutional symptoms - b symptoms, pruritus, alcohol induced painful lymphadenopathy
85% hodgkins
PET-CT scan
Ann Arbor stage:
stage 1 = single group of lymph nodes
stage 2 = >1 but on same side of diaphragm
stage 3 = nodes above and below diaphragm
stage 4 = extranodal spread -> bone marrow, liver (spleen does not count)
suffix A if none below, B if at least one
1. fever
2. night sweats
3. weight loss >10% in 6 months
(in a normal pet scan, the kidney, ureters, collecting duct and bladder light up as dye is excreted via this)
chemo
avoid radio due to risk of later cancer in tissues
causes of non hodgkins lymphoma?
1. chronic antigenic stimulation - bacterial or autoimmune
- h pylori - gastric MALT
- sjogerens - MZL - marginal zone lymphoma
- hashimotos - MZL of thyroid
- coelaic disease - small intestine EATL enteropathy associated T cell lymphoma
2. Direct viral integration in lymphocytes
- HTLV 1
3. Loss of T cell function leading to increased risk of EBV associated B NHL
- HIV
- transplant immunosuppresion
hodgkins lymphoma subtypes?
1. classical
2. lymphocyte predominant
Non hodgkins lymphoma subtypes
differences from hodgkins?
1. B cell - most common
2. T cell
in NHL, neoplastic lymphoid cells can circulate in blood vs hodgkins involving 1 lymph node group and spreading contiguously to adjacent nodes
Classification of common B cell NHLs
Low grade: (composed of small lymphocytes)
- Follicular lymphoma
- Small lymphocytic lymphoma/chronic - lymphocytic leukaemia
- Marginal zone lymphoma
High grade: (composed of large lymphocytes)
- Diffuse large B cell lymphoma
- Burkitt’s lymphoma
Aggressive:
- Mantle cell lymphoma
follicular lymphoma features? - clinical?
chromosomal translocation? (Chromosomal translocations in lymphoma typically involve translocation of oncogene to fuse with immunoglobulin promoter -abnormal b cell development)
Clinical
- painless Lymphadenopathy MA/elderly
Molecular
14;18 IgH-Bcl-2 gene
small lymphocytic lymphoma features
Clinical
MA/elderly; nodes/lymphadenopathy or blood
if little to no lymphadenopathy and high white cell count -> called CLL (composed of same cells)
Marginal zone Lymphoma features
commonly arise in extranodal sites eg G/MALT lymphoma (responsive to antibiotics for Hpylori)
associated with inflammation - gastritis , sjogrens
Mantle cell lymphoma features?
What molecule is expressed on histo pathology?
very aggressive
lymph nodes, GI tract
disseminated disease at presentation
histopathology - abberent CD5 and Cyclin D1 expression - D1 confirms diagnosis
t(11,14) IgH-CyclinD1
Burkitt lymphoma features?
Chromosomal translocation?
Jaw or abdominal mass
typically children or young adults
EBV association
histopathology - starry sky appearance
IgH -C-myc
fastest proliferating malignancy
Diffuse large B cell lymphoma features
MA/elderly, lymphadenopathy
histopathology - sheets of large lymphoid cells
T cell lymphomas
lymphadenopathy and extranodal sites
large t lymphocytes
associated reactive cell populations especially eosinophils
examples:
- adult t cell lymphoma - associated with HTLV
- mycosis fungoides
- enteropathy associated t cell lymphoma - complication of ceoliac disease
- anaplastic large cell lymphoma - nucleoli are variable in appearance but prominent
monitoring only is appropriate for asymptomatic small volume disease in which NHL subtype?
follicular lymphoma
- it is a low grade indolent lymphoma
- slow growing but not curable
*gastric malt is an exception for low grade lymphomas. it is indolent but you treat as it can be cured
Hodgkins lymphoma subtypes?
which is most common in women and young?
features? staining markers?
nodular sclerosis - most common in women and young people
lymphocyte rich
lymphocyte depleted
mixed cellularity
reed-sternberg cells - bilobed nuclei
CD15, CD30 (2 owl eyes) - positive in classical HL, negative in nodular LP HL
generally, lymphomas affect lymph nodes and leukemias affect blood
CLL
pathology?
features including lab findings?
immunophenotype?
key prognostic factor?
clinical features?
management? - name a BCR kinase inhibitor and a BCL2 inhibitor
proliferation of mature B lymphocytes
disease of elderly - most common cause of lymphocytosis in elderly
lymphocytosis
smear cells
lymphocytic infiltration of bone marrow
immunophenotype:
- abberant B-CLL cells which express CD5 (should be negative)
- CD5+/CD19+
deletion of 17p (Tp53) greatly lowers survival
mutation of IgH V gene lowers survival
lymphadenopathy
bone marrow failure
infection succeptibilty -> loss of b cell antibodies
1% transform to lymphoma
- supportive: vaccinations but not live, antibiotics
- chemo
- targeted therapy - BCR kinase inhibitors(BTK/ibrutinib), BCL2 inhibitors (Venetoclax - risk of tumour lysis syndrome!!!)
- CAR-T therapy
polycytheamia definition?
types?
raised HB and hematocrit concentrations
1. relative/pseudopolycythemia = lack of plasma (non-malignant)
2. True = excess erythrocytes, normal plasma vol.:
- secondary (non-malignant - increased EPO)
- primary myeloproliferative neoplasms (reduced EPO):
PV, ET, PMF (philadelphia chromosome negative)
CML (philadelphia chromosome positive)
risk factors for pseudo-polycythemia?
alcohol, obesity, diuretics
feature of secondary polycythemia?
causes?
raised EPO (EPO level important!! to rule out primary p.)
appropriately raised:
- high altitude
- hypoxic lung disease
- cyanotic heart disease
- high affinity hemoglobin
inappropriately raised:
- renal disease - cysts, tumours, inflammation
- uterine myoma
- other tumours (liver, lung)
myeloproliferative neoplasms give rise to mature cells but just an increase in proliferation (many cells) vs acute leukemia with immature cells
myeloproliferative neoplasms may cause hepatomegaly or spleenomegaly
proliferation in these neoplasms often involve mutation in?
Tyrosin kinases eg JAK2, calreticulin
Polcythemia vera
symptoms?
diagnosis
management?
- headaches, lightheadedness, TIA, stroke
- visual disturbances
- aquagenic pruritus
- FBC - raised HB and hematocrit
- genetic testing for JAK2
-(wcc and platelets may also be raised!)
reduce HCT
- venesecection, hydrocycarbamide
- keep platelets below normal range
Essential thrombocythemia
symptoms?
diagnosis?
managment?
- incidental finding on fbc. raised platelets BUT wbc and rbcs/hb MUST be normal
- thrombosis, arterial or venous - strokes, TIA, PE, DVT
- bleeding - mucous membrane and cutaneous as platelets may be dysfunctional
- headaches, dizziness, visual disturbances
aspirin - prevent thrombosis
hydroxycarbamide
anagrelide - inhbits platelet formation
Primary Myelofibrosis definition?
symptoms?
diagnosis?
managment?
malignant blood cells in bone marrow causing bone marrow fibrosis. thus symptoms:
- cytopenias!! - anemias, thrombocytopenias
- splenomegaly - may be MASSIVE (PMF and CML top of list for causes of massive spleen - eg spleen palpable in iliac fossa)
- hepatomegaly
(fibrotic bone marrow so hematopoeisis happening in liver and spleen)
- hypermetabolic state
blood film
- leucoerythroblastic film, tear drop cells
bone marrow
- dry tap
JAK2 mutation may be present
Jak2 inhbitor Ruxolotinib
Stem cell transplant
CML
symptoms?
diagnosis?
management?
- thrombosis, monocular blindness
- bruising, bleeding
- hypermetabolism
- massive spleenomegaly -/- hepatomegaly (if lymphadenopathy as well would mean lymphoma instead most likely)
Fbc - leukocytosis
blood film - neutrophils, myelocytes NOT blasts, basophilia
t(9,22) translocation which creates BCR-ABL fusion gene/oncoprotein!!
*in advanced phase, it can transform to a blast crisis/AML
tyrosine kinase inhibitor -> imatinib -> white cell count expected to fall
myelodysplastic syndromes classification?
features?
Must have:
1. cytopenia of at least on blood line. eg anemia
2. <20% blasts in blood or bone marrow but >5 (normal cut off). eg erythroblasts (can raise MCV)
3. morphological dysplasia of at least 10% in cell line OR molecular/genetic abnormalities
increased risk of transformation to acute myeloid leukemia - 1/3 OF people
disorders of the elderlybilobed neutrophils - Pelger Huet anomaly
abnormal granulation in neutrophils eg hypogranular
dysplastic rbcs and megakaryocytes
refractory anemia -> ringed sideroblasts (type of erythroblast). can also cause raised ferritin. if ferritin is too high, can cause liver failure etc -> treat at certain level
MDS treatment?
blood product support
antimicrobial therapy - due to succeptibility to infection
biological modifiers eg immunosuppressive therapy
stem cell transplant
chemo
primary causes of bone marrow failure
. PRIMARY
Congenital: Fanconi’s anaemia (multipotent stem cell)
Diamond-Blackfan anaemia (red cell progenitors)
Kostmann’s syndrome (neutrophil progenitors)
Acquired: Idiopathic aplastic anaemia (multipotent stem cell)
secondary causes of bone marrow failure
Marrow infiltration:
Haematological (leukaemia, lymphoma, myelofibrosis)
Non-haematological (metastatic solid tumours, secondary fibrosis)
Radiation
Drugs
Chemicals (benzene)
Autoimmune
Infection (Parvovirus, Viral hepatitis, HIV)
name drugs that can cause bone marrow failure
PREDICTABLE (dose-dependent, common)
Cytotoxic drugs
ANTIBIOTICS
Chloramphenicol
Sulphonamide
DIURETICS
Thiazides
ANTITHYROID DRUGS
Carbimazole
Aplastic anemia causes?
presentation?
all age groups affected
mostly idiopathic
other causes:
Inherited: Dyskeratosis congenita (DC). Fanconi anaemia (FA), Shwachman-Diamond syndrome
secondary: drugs, radiation, infection
PNH
triad of anema, leukopenia, low platelets (bone marrow failure)
hypocellular bone marrow
differentials for pancytopenia and hypocellular bonemarrow? (you dont need to memorise)
Aplastic anemia
Hypoplastic MDS / Acute Myeloid Leukaemia
Hypocellular Acute Lymphoblastic Leukaemia
Hairy Cell Leukaemia
Mycobacterial (usually atypical) infection
Anorexia Nervosa
Idiopathic Thrombocytopenic Purpura
severe aplastic anemia criteria?
2 out of 3 peripheral blood features
1. Reticulocytes < 1% (<20 x 109/L)
2. Neutrophils < 0.5 x 109/L
3. Platelets < 20 x 109/L
Bone marrow <25% cellularity
aplastic anemia treatment
blood products + iron chelation therapy
antimicrobials
immunosuppresive treatment - older patients
stem cell transplant - young
androgen treatment
aplastic anemia complications
relapse
risk leukemia, mds, pnh, solid tumours
cure rate for sibling related stem cell transplant for aplastic anemia in patients under 40?
70%
Fanconi anemia
features?
complications?
most common genetic cause of aplastic anemia
Short Stature
Hypopigmented spots and café-au-lait spots
Abnormality of thumbs
Microcephaly or hydrocephaly
Hyogonadism
Developmental delay
No abnormalities 30%
AA, MDS, leukemia
dyskeratosis congenita features?
genetic basis?
Marrow failure
Cancer predisposition
Somatic abnormalities
Patients may present with the Classical Triad of
Skin pigmentation
Nail dystrophy
Leukoplakia
telomere shortening (also seen in idiopathic AA) -> bone marrow failure
women with facial plethora, high platelets, high neutrophils, high Hb,
what is a likely cause?
polycythemia vera
- high rbc count is not feature of cml
tests:
- analysis for JAK2 mutation
- bone marrow aspiration and trephine biopsy
- serum erythropoeitin
may do tests to exclude secondary polycythemia eg CXR if smoker
extensive atheromatous disease, diabetes mellitus
post abdominal aortic aneurysm repair:
presenting with acute renal impairment, sepsis, respiratory distress
blood film:
toxic granualation and vacuolation
left shit
rouleaux
most likley cause of high wcc?
reactive neutrophilia
64 year old woman with splenomegaly
leucocytosis with myelocytes and basophilia
most likely diagnosis?
chronic myeloid leukemia
its NOT acute myeloid leukemia because platelet count is normal
man with bruising with isolated low platelets? week later, neutrophils, rbcs still normal. most likely diagnosis
ITP
baby/ neonate with brusies, differentials?
non accidental injury
coagulation abnormality
thrombocytopenia
woman with 18 month old baby
microcytic hypochromic anemia some anisocytosis, some elongated rbcs
questions to ask?
a differential?
bleeding - especially menstrual bleeding
history of pregnancies
diet
IDA
differentiating osteomyelitis and septic arthritis in kids
osteomyelitis will show bone changes vs septic arthritis wont
osteomyletis more common in kids
causes of polycythemia in neonates?
twin to twin transfusion
intrauterine hypoxia
placental insufficiency
learn about hemoglobinopathies and thalessemias in children, learn about hemolytic anemias
why is sickle cell different in child vs adult?
red marrow that in childhood that can be infarcted
B12 diagnosis signs
hypersegmented neutrophils - blood film
giant metamyloctes - bone marrow
how does autologous transplantation work?
USED IN?
growth factor infusion -> collect stem cells in remission -> thaw and reinfuse and give high dose chemo
used in:
- acute leukemia, myeloma, lymphoma, CLL
- solid tumours - germ cell tumours
- autoimmune diseases - Scleroderma, MS
how does allogenic transplantation work?
high dose chemo and radio -> infuse bone marrow or stem cells from HLA matched donor
used for:
all blood cancers
bone marrow failure - eg aplastic anemia
congenital immune deficiencies
how do you gain hematopoeitic stem cells?
1. Bone marrow
2. peripheral blood
give g-scf -> cells circulate in blood stream -> harvest peripheral blood
3. umbilical cord
Graft vs host disease
symptoms?
treatment?
strongest prognostic factor?
acute = skin, GI tract (nausea -> bloody diarrhea), liver
chronic = skin, mucous membranes, lungs liver eyes joint, immune dysregulation, immune dysfunction
worry of gram -ve infections
corticosteroids etc
prior acute gVHD = strongest prognostic factor
risk factors for GVHD?
conditioning regimen - if it causes a lot of cell death/toxicity will increase GVHD
sex mismatch
with PBSC worse than bone marrow
if patient has concomitant viral infection
higher HLA mismatch
recipient age and disease phase
Methods to prevent Acute GVHD?
methotrexate
corticosteroids
calcineurien inhibitors (cyclosporin A, tacrolimus, sirolimus)
CsA + MTX
(donor) T cell depletion!!!
post-transplant cyclophosphamide
onset timeline of infections post transplant
bacteria - early onset. gram +ve typically from vascular access. gram -ve from GI tract and are much more dangerous!!/cause most deaths eg ecoli
viruses - tend to come later except herpes simplex = early
post stem cell transplant bugs
CMV - pnuemonitis, retinitis etc. more common in seropositive than seronegative people
EBV
resp viruses
BK and hemorrhagic cystitis
adenovirus
changes to fbc during pregnancy?
1. thrombocytopenia - and increased platelet size
2. mild anemia - red cell mass increases but plasma volume more
3. macrocytosis - phyisiological but also due to folate/b12 deficiency
4. neutrophilia
impacts of iron deficiency during pregnancy?
IUGR, prematurity, ppH
define anemia in pregnancy
HB <110 in 1st trimester
and <105 in second and 3rd
causes of thrombocytopenia in pregnancy?
physiological/gestational thrombocytopenia = most common. lower platelet count, less likely to be
preeclampsia
ITP
microangiopathic syndromes - deposition of platelets in blood vessels. platelets shear rbcs - hellp, ttp, pet, hus, aflp, sle, etc
other things that could also happen when non pregnant: bone marrow failure, leukemia etc
ITP treatment in pregnancy?
IV immunoglobulin
steroids
coagulation changes in pregnancy?
increase in procoagulant factors and decrease in anticoagulants eg protein S
VTE highest risk time during pregnancy?
risk factors for VTE
investigations
DVT is more common on which leg?
how to treat women with risk f actors for VTE?
6 weeks post partum period
BMI!!!, hyperemesis gravidarum, preeclampsia, operative delivery, previous thromboisis/fh, age >35, parity, multiple pregnancy, ovarian hyperstimulation syndromes eg from drugs given in IVF, medical problems eg HBSS, nephrotic syndrome
Doppler, VQ
ddimer not useful as elevated in pregnancy
left dvt
prophylactic LMWH, Mobilise early, maintain hydration. Stop LMWH For labour, epidural, delivery
condition caused by warfarin use during pregnancy?
chondrodysplasia punctata
causes of pospartum hemorrhage?
4Ts
Tone = Uterine aTony!
Trauma = Laceration/Uterine rupture!
Tissue = Retained placenta
Thrombin - coagulopathy = DIC in abruption or amniotic fluid embolism. dilutional coagulopathy after resus
causes of DIC?
amniotic fluid embolism
abrupt placenta
retained dead fetus
severe preclampsia
sepsis
(they all cause exposure of tissue factor)
+ coagulation changes in pregnancy is a cause
amniotic fluid embolism presentation?
sudden onset shivers, vomiting, shock, DIC
(tissue factor in amniotic fluid)
how to differentiate IDA from thalassemia trait
IDA = Low HB, low or normal RBC
Thalassemia trait = normal HB, increased RBC
- increased HBA2 in b thal trait
- normal in alpha thal trait
Multiple myeloma features
risk factors
symptoms
complications?
imaging?
bence jones protein in urine
serum IgG or IgA - paraprotein or m spike
monoclonal kappa or lambda serum free light chains
age - median = 67
genetics - black
obesity
men> women
crab
hypercalcemia
renal disease
anemia
bone disease
immunosuppresion and infections
AL amyloidsois - renal(due to serum free light chains deposits) , heart failure, cord compression, hypercalcemia
FDG-PET
Diagnostic criteria for MGUS?
risk factors for progression to MM?
1. <10% plasma cells
2. Monoclonal protein spike <30 g/L
3. no CRAB symptoms or organ damage
* No evidence of other B-cell proliferative disorder
Diagnostic criteria for smouldering myeloma?
1. >10% plasma clone cells
2. +/- M spike (monoclonal protein spike) >/= 30
3. no organ damage or CRAB symptoms!! vs multiple myeloma
MGUS -> smouldering myeloma > myeloma
no paraprotein in serum or urine
what two conditions preceed multiple myeloma?
MGUS and smouldering myeloma
AL amyloidosis symptoms?
nephrotic syndrome
HF
sensory neuropathy
abnormal LFTS
macroglossia
name a feature of high risk multiple myeloma
t(4,14) IGH/FGFR3 and del17p in TP53
median survival of people diagnosed with myeloma today?
list two causes of
microcytic anemia
normocytic anemia
macrocytic aneamia
what are the b cell markers?
T cell markers?
what is TDT a marker of? what does it suggest?
what is surface Ig a marker of?
B = CD19 and 20
T = CD3, CD4, CD8, CD5
TDT = marker immature B and T lymphoblasts. always suggestive of ALL
Surface Ig = mature B cells and plasma cells
36 year old woman, fatigue, joint pains with malr rash, menorrhagia, ESR 80. Bloods show low hb, raised LDH, bilirubin, reticulocytes. blood film shows rbcs with no central pallor. most likely diagnosis
hemolytic anemia -> spherocytocsis
autoimune spherocytosis - Dat +ve
inherited spherocytosis - Dat -ve
learn about hemolytic anemias, both inherited and acquired
Give two examples of a DAT -ve acquired hemolytic anemia. (non immune)
hypersplenism, malaria, MAHA
low ferritin confirms what condition?
normal or high ferritin means what?
What happens to transferrin/transferrin saturation in IDA and ACD?
IDA
may be IDA or ACD
high in IDA
low/normal in ACD
name some non malignant causes of pancytopenia
1. B12 Deficiency/folate. anemia will be macrocytic
2. aplastic anemia
pancytopenia + tear drop cells on blood film points to?
myelofibrosis
healthy 58 year old man. routine fbc -> high wcc with high neutrophils. blood film shows excess basophils and myelocyte presence and neutrophils. everything else normal.
what is the single most useful test to confirm diagnosis?
BCR ABL 1 PCR assay - for t(9,22)
- CML = most likely diagnosis
*Hb are typically well preserved or raised in CML
treatment for CML?
tyrosine kinase inhibitor
What mutation is commonly tested for in CLL?
CLL symptoms
what can it progess into
treatments?
TP53 mutation status - more aggressive disease with mutation
Proliferation of mature non functional b cells. can cause lymphadenopathy and spleenomrgally. increased risk of infection due to hypgammaglobulinemia
lymphoma = richter transformation
BCR kinase inhibitors - ibrutinib
bcl2 inhibitors - venetoclax
which factors carry the highest risk of thrombosis?
antithrombin deficiency
family history of thrombosis
risk of recurrence is highest after what type of thrombotic event?
idiopathic - long term anticoagulation
COCP, flights trauma -> minor precipitants -> 3 months anticoagulation
- no need for long term anticoagulation after surgery
